Cancer is a group of diseases characterized by the unusual control of cell growth. There are over 100 different types of cancers, which are classified by the type of cells initially affected such as bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney (renal cell) cancer, leukemia, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, thyroid cancer, skin cancer, non-hodgkin's lymphoma and melanoma and head and neck cancer. Squamous cell carcinoma represents more than 90% of all head and neck cancers. Head and neck squamous cell carcinomas make up the vast majority of head and neck cancers, and arise from mucosal surfaces throughout the anatomical region. These include tumors of the nasal cavities, paranasal sinuses, oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx.
In fact, head and neck cancer (HNC) is the sixth most common cancer worldwide, with an annual incidence of >640,000 cases worldwide. More than 90% of head and neck cancers are of squamous histology (HNSCC). Thirty-five percent to 45% of head and neck cancer patients ultimately die from their disease. In the United States alone, squamous cell carcinoma of the head and neck comprises about 4% of all malignancies. This corresponds to an estimated 17 per 100,000 persons with newly diagnosed squamous cell carcinoma of the head and neck per year (Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008, CA Cancer J. Clin. 2008 March-April; 58(2):71-96). Squamous cell carcinoma of head and neck (SCCHN) remains a challenging clinical problem, due to persisting high rate of local and distant failure, as well as the occurrence of second primaries. Some molecular targeted therapy used in squamous cell cancers of the head and neck include cetuximab, bevacizumab, erlotinib and reovirus. The best quality data are available for cetuximab, a recombinant monoclonal antibody, since the 2006 publication of a randomized clinical trial comparing radiation treatment plus cetuximab versus radiation treatment alone (“Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck”. N Engl J Med 2006; 354 (6): 567-78). Another study evaluated the impact of adding cetuximab to conventional chemotherapy involving use of cisplatin versus cisplatin alone. This study found no improvement in survival or disease-free survival with the addition of cetuximab to the conventional chemotherapy (J Clin Oncol. 2005; 23 (34): 8646-54). However, another study completed in March 2007 found that there was an improvement in survival. This study is referred to as EXTREME (Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer) study which is a European multicenter phase III trial.
Further, it is well established in the art that CDK (Cyclin-dependent kinase) inhibitors are useful in anti-proliferative therapies for diseases characterized by excessive cell growth such as cancers and immunological disorders involving unwanted proliferation of leukocytes. Flavone derivatives useful as CDK inhibitors are described in PCT Patent Publication No. WO2004-004632 (U.S. Pat. No. 7,271,193) which patent application specifically relates to the compounds for inhibition of cyclin-dependent kinases, process for their preparation, methods of inhibiting cyclin-dependent kinases and of inhibiting cell proliferation, use of such compounds in the treatment of proliferative disorders including cancers. PCT Published application No. WO2005-053699 (U.S. Pat. No. 7,772,207) relates to a pharmaceutical product comprising a CDK inhibitor and 1-(2-C-cyano-2-dioxy-p-D-arabino-pentofuranosyl)-N4-palmitoyl cytosine or a metabolite thereof, as a combined preparation for simultaneous, sequential or separate administration. PCT Published application No. WO2008-122779 (U.S. Patent Appl. Pub. 2010-0143350) describes combination of CDK inhibitor with a tyrosine kinase inhibitor and use thereof in the treatment of proliferative disorders. PCT Published application No. WO2008-139271 (U.S. Patent Appl. Pub. 2010-0305057) relates to pharmaceutical combination comprising a cytotoxic antineoplastic agent selected from paclitaxel, docetaxel, doxorubicin or gemcitabine and at least one cyclin dependent kinase (CDK) inhibitor for use in the treatment of cancer. PCT Published application No. WO2010-128443 describes a combination for the treatment of cancer wherein the combination comprises radiation and at least one cyclin dependent kinase (CDK) inhibitor or a pharmaceutically acceptable salt or a solvate thereof.
Although combinations of anticancer agents have been proven to have a significant advance in various cancer treatment protocols including squamous-cell carcinoma of the head and neck (SCCHN), there are still several unmet needs and room for improvements in medications for the treatment of SCCHN, which are difficult to treat, or which have shown resistance to treatment with the conventional antineoplastic agents. More particularly, the development of novel combination approach for delivering known anticancer agents having different mechanism of action would represent an important advance in the art. Although the protocol involving combination of anticancer agents having different mechanism of action may work in case of some combinations, it may not work in the same manner for other combination of anticancer agents and such combination may not always result in a combination having advantageous therapeutic effects. However, the inventors of the present invention have found that a pharmaceutical combination of anticancer agents comprising a cyclin dependant kinase (CDK) inhibitor and one or more antineoplastic agent provides greater efficacy than when the CDK inhibitors or the antineoplastic agents are used alone for the treatment of squamous-cell carcinoma of the head and neck (SCCHN).